Threeultrasoundcontrastagents(Definity,OptisonandLumason)areFDAapprovedfor echocardiographyintheU.S.Definitycurrentlyhasover75%marketshare.Definity?sdominanceinthemarket isduetoitseaseofadministrationviaIVinfusionandrobustultrasoundcontrast.Definityhasshelf-lifeof2 yearsandmustbestoredunderrefrigeratedconditions.Definityhasanunpleasantsideeffectofbackpainin about2%ofpatients.Insomegroups,e.g.patientswithsicklecelldisease,therateofsideeffectsismuch higher,e.g.about20%.Themostlikelyetiologyofthebackpainiscomplementactivation.Definityisstabilized bythreephospholipidsoneofwhichisdipalmitoylphosphatidicacid(DPPA).Theinvestigatorsinthisproposal haveshownthatDPPAshortensthestoragelifeofDefinityandlikelycausesthesideeffectofthebackpain. MicrovascularTherapeutics(MVT)hasdiscoveredthatnotonlyisDPPAthemostrapidlyhydrolyzedlipidin theDefinityformulationbutthatDPPAalsoacceleratesthehydrolysisoftheotherlipids.WhenDPPA hydrolyzesitformslyso-PA-apotentstimulatingmoleculecausinginflammationlikelyresponsibleforthe adversesideeffects.MVThasinventedastable,neutralMB(MVT-100).ComparedtoDefinity,MVT-100is fourtimesmoreresistanttohydrolysis.Inamodelofcomplement-mediatedrenalretentionMVT-100hadfewer bioeffectsthanDefinity?whichshouldtranslateintosignificantlylessadverseevents.Echocardiographyin pigsshowsthatMVT-100iscomparable,ifnotsuperiortoDefinity,inprovidingLVopacificationand myocardialperfusioncontrast.MVThasreceivedguidancefromtheFDAthatMVT-100canbedeveloped viathe505(b)(2)pathway,noadditionalanimalstudiesarerequired;?anacceleratedclinicalprogram canbeusedtoleadtoapproval.MVT-100willserveasaplatformfordevelopmentoftheranostics. SpecificAims:1.GMPmanufactureMVT-100,fileIND.2.Doserangingstudyin32volunteers(bolusand infusion,DefinityvsMVT-100)3.Pivotalstudyin61patientswithsuboptimalechocardiograms;?significant improvementinLVborderdelineationin>85%ofsubjects.4.FileNDA Rationale:MVT-100isanimprovedproduct.PerfluoropropaneistheAPIandthelipidsareexcipientsinthe product.The505(b)(2)pathwayallowsforanacceleratedapprovalpathwayforsuchproducts.UponNDA submission,typical11-monthreviewperiodbytheFDAbeforeapproval.Thedevelopmentpathwaywillyield identicallabelclaimsasthoseforDefinity.Additionallabelclaimscanbepursuedlaterorinparallel. Expectedoutcomesofresearch:DevelopmentofanFDAapprovedimprovedperflutrenproduct,MVT-100 withlongershelf-life(potentialforroomtemperaturestorageandterminalsterilization?increasingsafetyofthe product)anddecreasedadversesideeffects.Sincetheproductiselectrostaticallyneutral,MVT-100willalso serveasarobustplatformfordevelopmentofmolecularimagingtargetedultrasoundcontrastagents andtheranosticagents.